Abstract LB-320: PPTC testing of an OLIG2 inhibitor CT-179 in patient-derived orthotopic xenograft mouse models of pediatric GBM

Abstract

Abstract Background: Oligodendrocyte Lineage Transcription Factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells (GSCs) that has been shown to be essential for tumorigenesis and a significant driver of tumor growth, GSC motility, and resistance to radiation. We evaluated the efficacy of the OLIG2 inhibitor CT-179 on survival times in pediatric glioblastoma (pGBM) patient-derived orthotopic xenograft (PDOX) models. Methods: OLIG2 mRNA expression levels were examined by gene expression profiling. In vitro activity was analyzed in matched monolayer cells and 3D neurospheres from 8 PDOX models treated with CT-179 (0-10 µM) alone as well as in combination with radiation (XRT) (0-8 Gy). For in vivo drug testing, 105 pGBM cells were implanted into the brains of SCID mice. Brain penetration of CT-179 was evaluated in PDOX tumors and normal mouse brain tissues using blood concentration as reference. Therapeutic efficacy was examined in 4 PDOX models. Vehicle or CT-179 was administered by oral gavage starting one week post tumor implantation. CT-179 was dosed at 200 mg/kg every 4 days (q4d). In one model, a dose of 240 mg/kg every 3 days (q3d) was also used. XRT (2 Gy/day x 5 days) was given alone and in combination with CT-179. Median survival was determined using the Kaplan-Meier method, with the significance level for combination testing experiments set at 0.01 to account for multiple comparisons. Results: High level OLIG2 mRNA expression was detected in all PDOX tumors. CT-179 inhibited cell viability in a time- and dose-dependent manner in all 8 pGBM cell lines (IC50 0.03-10 µM). XRT potentiated the effects of CT-179 at low/moderate drug doses (0.03-1 µM). Compared with a mean serum concentration of 361.3 ± 1.5 ng/mL, oral gavage of CT-179 led to high tissue concentrations in the cerebrum (3,232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ±309 ng/g) and PDOX tumors (1,814 ± 110.3 ng/g). In the PDOX models, the ratios of the median survival time for single agent CT-179 (200 mg/kg q4d) groups to their respective control groups (T/C) ranged from 0.61 to 1.19; no comparisons reached statistical significance. In one of the models, when a higher dose (240 mg/kg q3d) was used a longer T/C ratio (1.06 vs 1.02) was observed. In 1 of 4 PDOX models, combining CT-179 and XRT significantly improved survival times when compared with the control and single agent CT-179 groups, and for another PDOX there was a trend for improved survival for the combination compared to control. Conclusion: The molecular target of CT-179, OLIG2, was over-expressed in multiple pGBM xenografts. CT-179 inhibited cell viability of pGBM cells in vitro, and effectively penetrated and accumulated in CNS tissues and PDOX tumors. Single agent CT-179 showed limited impact on survival for the pGBM xenografts that were studied. The combination of CT-179 and XRT increased survival times in some pGBM PDOX models. Citation Format: Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank Braun, Mari Kogiso, Sarah Injac, Mary Sobieski, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Stephen Erickson, Beverly Teicher, Malcolm A. Smith, Xiao-Nan Li. PPTC testing of an OLIG2 inhibitor CT-179 in patient-derived orthotopic xenograft mouse models of pediatric GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-320.